The Nodulus and Uvula (NU) are regions of the cerebellar cortex essential for vestibular processing and spatial navigation. They process motion signals arriving from vestibular afferents (otoliths and semicircular canals), and send outputs to cerebellar and brainstem vestibular nuclei. The long-term goal of this project is to understand the role of the NU in spatial navigation and vestibular processing. Recently it has been shown that NU Purkinje cells (the sole output of the cerebellar cortex) exclusively encode inertial motion (translation- selective Purkinje cells) and gravity (tilt-selective Purkinje cell) by combinng otolith signals with a transformed signal from the semicircular canals. It is still unknown however, whether translation and gravity signals are computed in NU or they are sent there already computed (e.g. from the vestibular nuclei). This grant proposal is designed to tackle this question through investigating the role of local GABAergic inhibition in the neuronal response properties of Purkinje cells and granular layer interneurons, and characterizing the response of mossy fibers. We will test the hypothesis that GABAergic inhibition near NU Purkinje cells (Aim 1) and in the Granular Layer (Aim 2) participate in vestibular afferent signal transformations necessary to compute inertial motion and gravity. We will characterize the response properties of translation- and tilt-selective NU Purkinje cells (Aim 1a, b) and Granule Layer Interneurons (Aim 2b) to vestibular stimulation with and without application of GABA-A and GABA-B receptor antagonists. These drugs will be delivered iontophoretically using small current injections (50-100nAmp) to affect only receptors located near the recording site. The project focuses on studying the effect of blocking GABA-A and GABA-B receptors because they are the most commonly found inhibitory receptors in the cerebellar cortex. We will test if these receptors belong to pathways performing different computations, or if they work to complement each other in order to compute translation and tilt. We will also study what type of vestibular information is send by mossy fibers to NU by recording mossy fiber responses to vestibular stimulation. The proposed experiments are designed to complement each other and strengthen the power of interpretation. Based on preliminary data, blockage of GABAergic inhibition will remove the ability of NU Purkinje cells to estimate translational and gravitational acceleration, and will change the vestibular driven responses of GLI. Together, these experiments will elucidate the role of inhibitory interneurons in the signal transformations carried out by NU. Indeed, they have the potential of unveiling general rules of cerebellar function. Our preliminary data together with data collected by a precedent R03 (see progress report) are the strongest evidence available today that some of the computations necessary to form an internal estimation of tilt and translation take place in NU.